Immediate Goals: To examine the mechanism of ischemic mitral regurgitation (MR) with the goal of designing and implementing more effective therapy to reduce adverse impact on patients. Career Development Goals: To provide sufficient time for mentoring and research activities. Research Project: Mitral valve function can be understood in terms of the force-balance concept in which tethering forces from the papillary muscles balance left ventricular valve closing forces. In ischemic MR, this force balance may be altered in ways that impair the ability of the mitral leaflets to close effectively at the annular level. This proposal uses a combined, parallel clinical and experimental approach to evaluate the mechanism, progression and therapy of ischemic MR, all relating to the central hypothesis that ischemic MR is caused by an abnormal relationship of the mitral valve to its supporting ventricular structures. These altered relationships involve both abnormal tethering forces due to displacement of the papillary muscles as well as reduced closing forces due to LV contractile dysfunction. Specific testable questions related to this hypothesis include: 1) The progression of mitral regurgitation in patients with acute myocardial infarction relates to abnormalities in the mitral valve-ventricular relationship; 2) These mechanisms also cause persistent MR despite coronary revascularization surgery, thereby impairing exercise capacity and raising pulmonary pressures; 3) Both an externally applied device and afterload reduction provide effective means of reducing ischemic mitral regurgitation by normalizing these relationships between the valve and the ventricle; cutting a minimum number of critically positioned strut chordae also has the potential to relieve tethering, and opens the way to potential minimally invasive percutaneous approaches. The aims of the mentored award will be met by allowing the PI to translate his experimental expertise to direct clinical studies of progression and functional outcome of ischemic MR, and to make the transition from mechanism to therapy in models reflecting the clinical situation, with the ultimate goal of patient applications.